Category: Formulation and Quality
Purpose: Caffeine citrate (CC), the component of a number of analgesic formulations, is a central nervous stimulant and helps to restore alertness(1). The main purpose of this study was to develop a robust immediate release formulation of CC by a hot-melt extrusion (HME) process and fused deposition modeling (FDM) 3D printing method (3DP).
Methods: The filaments used for 3DP were prepared by HME techniques. The extruder used in this study was a co-rotating, twin screw extruder with 11 mm diameter screws, a length/diameter ratio of 40/1, and eight electrically-heated zones (Thermo Fisher Scientific, Waltham, MA, USA). Physical mixtures, F1 ((CC (15% w/w), HPC LF (65% w/w), HPMC K4M (20% w/w)) and F2 ((CC (10% w/w), HPC LF (70% w/w), HPMC K4M (20% w/w)) were extruded at 155 °C for all zones at a screw speed of 50 rpm, respectively. A 1.5 mm-round die was used to extrude filaments for the 3D printer. The torus shape, with the largest surface area to volume ratio compared to normal 3DP tablet shapes(2), has the best properties for immediate release. The torus tablets were designed using Microsoft 3D Builder (Microsoft, Redmond, WA, USA). Tablet dimensions (Max diameter: 10mm, height: 5mm, radius (the distance between the tablet center to the tube center): 3.5mm, tube thickness: 3mm, wall thickness: 0.2mm) were determined (Figure 1). Tablets were fabricated from the extruded filaments using a commercial FDM-3D printer (Prusa i3 3D desktop printer, Prusa Research, Prague, Czech Republic). The printing temperature was 200℃ and the tablets were printed to 10%, 50% and 100% infill. A TA-XT2i analyzer (Texture Technologies, Hamilton, MA, USA) and a TA-95N 3-point bend probe set were used to test the brittleness of the extruded filaments. Samples of extruded filaments were placed on the sample holder of the 3-point bend tester with a 25-mm gap(3). Ten filaments of each formulation were tested. Poly Lactic Acid was used as a reference to compare the differences between commercially available filaments and extruded filaments. The thermal characterization of the filaments was performed by differential scanning calorimetry (DSC) and thermogravimetric analysis. The in vitro drug release from different 3D structured tablets was determined using a United States Pharmacopeia (USP) dissolution apparatus I in simulated gastric fluid (0.1N HCl, 900mL) and pH 6.8 phosphate buffer, with the temperature maintained at 37 ± 0.5℃ and a basket rotation speed set to 100 rpm.
Results: The degradation temperature of CC is above 250℃, so it was suitable to set the printing temperature at 200℃. The F1 filaments had proper ductility and stiffness and could be printed well while F2 filaments could not. The stress of F1, and F2 were 137.5 ± 10.5(g/mm2) and 128.74 ± 6.7(g/mm2) and the breaking distances were 4.9 ± 0.3 mm and 4.9 ± 0.6 mm, respectively. An independent t-test showed that there was a significant difference between the stress of F1 and F2 filaments (t=2.237, p=0.038< 0.05). The tablets with 100% infill density exhibited a very solid structure. Tablets with 50% and 10% infill density showed a larger cross section of porous structures inside. Drug release kinetics from tablets showed 100% infill tablets had the lowest dissolution rates in simulated gastric fluid in vitro tests (Figure 2). It was observed that the drug release of 10% infill, 50% infill and 100% infill tablets at the 120 min time point were 91.1 ± 3.3%, 83.3 ± 5.8% and 77.5 ± 2.0%, respectively. The drug release in pH 6.8 buffer was fast from 10% infill with around 70.0% within 30 min. The DSC thermogram of CC (Figure 3) exhibited an endothermic melting peak at around 168 °C. However, the peak was absent in the extrudates, indicating the transformation of CC from the crystalline to the amorphous state.
Conclusion: It was observed that the CC tablets were successfully formulated and produced using HME and fused deposition modeling 3DP. Only the F1 filaments could be printed. The tablets showed a high dissolution rate in pH 6.8 buffer. The 10% infill tablets (with maximum porosity and interspace, compared with 50 and 100% infill) exhibited the best release properties.
Honghe Wang– Oxford, Mississippi
Honghe Wang– Oxford, Mississippi
Nagireddy Dumpa– Mr, University of Mississippi, Oxford, Mississippi
Suresh Bandari– Post-doc, University of Mississippi, Oxford, Mississippi
Michael Repka– Professor, University of Mississippi, Oxford, Mississippi
Thomas Durig– Wilmington, Delaware